Hydrogenation products of delta 6-estrone and method of preparing same



Patented Aug. 24, 1943 UNITED HYDROGENATION PRODUCTS 0F A6- ESTRONE ANDl/IETHOD OF PREPAR- ING SAME Erwin Schwenk, Montclair, N. J .,as s'ignor to Schering Corporation, Bloomfield, N. J., a

corporation of New Jersey No Drawing.- Application February 14, 1940,

serial No. 318,918

6 Claims.

The present invention relates to the partial hydrogenation products of A -e'strone, and to a method of producing the same. t

'It is the general object of the invention to produce partial reduction products of A -estrone in which the phenolic character of the'first ring is preserved.

I have found that A -estrone can under certain conditions be partially hydrogenated to yield M-estradio-l, and can also be more highly hydrogenated to form estradiol, these products bein physiologically active and serving also as intermediates for the production of other physiologically active compounds.

I have found that it is possible to prepare the known physiologically highly effective alpha estradiol and its isomer, the beta estradiol, and also the hitherto unknown A -estradiol, by starting with the easily obtainable A -estronel compound may be prepared from fi-keto-estrone (see my copending application, Serial No. 273,- 416, filed May 13, 1939, entitled Oxygenated estrogenic hormones and method of preparing same) by hydrogenating and splitting out water from this compound, or it may be prepared from other starting materials, as, for instance, equilin. I have found that it is possible to introduce two or four hydrogen atoms in A -estrone in such a way that only the keto-group in 17 position, or such keto group and the double bond in ring B are hydrogenated. When two hydrogen atoms are added, the resulting compound is the A estradiol which exists in two isomeric forms. The substance shows estrogenic activity when tested by the Allen-Doisy test. This reduction may be carried out by introducing two hydrogen atoms into the molecule with the aid of the Meerwein- Ponndorf reaction, that is, by heating'the com-' pound or its B-derivatives such as esters or ethers with an alcohol and a metal alcoholate, as with isopropyl alcohol and aluminum isopropylate. The isopropyl alcohol is oxidized to acetone, while the starting compound is reduced to the secondary alcohol. Another method of manufacture is to dissolve the compound in alkali solution and add a finely divided metal or metal alloy, such as zinc, aluminum, and the so-called Raney alloys, for example, nickel-aluminum alloy with a content of 50% aluminum. The hydrogen which is evolved acts to reduce the keto group only, and the double bond is not attacked. Finally, catalytic reduction may be used, metal catalysts being employed under such mild conditions (both the nature of the catalyst and the temperature and pressure being taken into con- This (c1. zoo-397.5)

sideration) that only the keto group, or at most the" keto group and the A double bond are hydrogenated. Thus where noble metal catalysts are used, such as metals of theplatinum group (for example, platinum andpalladium) or if the reaction is carried out under higher temperatures and pressure, in the case of a nickel catalyst, 4 atoms of hydrogen are absorbed and the alpha estradiol is immediately obtained.

The following examples will serve to illustrate in detail several methods of carrying out the invention, but are not intended to indicate the scope of the invention:

Example 1 1 gram of A -estrone of a M. P, 265 C. and a rotation of +150 is dissolved in 200 cc. of 10% potassium hydroxide solution, and 5 grams of a nickel-aluminum alloy in finely powdered form' are added in small portions to the well-stirred solution. After the powder has all been introduced, the reaction mixture is heated on the water bath and stirred for A; hour more. It is then filtered from the nickel, and acidified with hydrochloric acid to slight congo reaction. After cooling, the new compound crystallizes out in beautiful crystals. The melting point of the product is not very sharp, the product melting with decomposition. When it is dissolved in sulfuric acid, a yellow coloration is obtained.

Example 2 1 gram of A -estrone is dissolved in a mixture of 100 cc. of isopropyl alcohol and 20 grams of 1 gram of A -estrone is dissolved in alcohol, 200 mgm. of a platinum catalyst are added and the solution shaken with hydrogen at room temperature. 4 atoms of hydrogen'are absorbed. After filtration from the catalyst, the solution is precipitated by addition of water, and the substance filtered. A mixture of alpha and beta estradiol is obtained, meltin at 172 C., which may be separated into alpha and beta estradiol by known methods, as by fractional distillation under vacuum.

The A -estradiol, obtained, for instance, according to Examples 1 and 2, can be partially hy drogenated to estradiol by subjecting the sam to hydrogenating agents capable of saturating dou ble bonds, such as catalytically activated hydrogen, as in Example 3.

In place of the A -estrone, the corresponding 3- ester, for example, the acetate, benzoate, or pro- ,7 pionate, can be employed, and Will yield a corresponding 3-ester of A -estradiol. Similarly, the 3-ethers, such as the methyl andethyl others, can be employed as the starting materials. The

3-substitution products of the h -estradiol can residue into the ll-position of the dlol. In this manner the 17-propionate, for example, and likewise the benzoate, can be produced.

The sodium compounds of the A -estradiol produced in accordance with the procedures set forth in Example 1 can themselves be isolated as such, either by evaporation of the solution, or by salting out by the addition of soluble salts.

' I claim; 1. The method of producing unsaturated dlols of the estrane series which comprises subjecting A -estrone to the action of an alcohol in the presence of a metal alcoholate, and recovering the A -estradiol so produced. I

'2. The method of producing unsaturated diols of the estrane series which comprises subjecting M-estron to the action of an alcohol in the presence of an aluminum alcoholate, and recovering the A -estradiol so produced.

3. A compound of the group consisting of A"- estradiol and its 3-substitution products capable of conversion to M-estradiol with the aid of hydrolysis.

4. 3-acyl-A -estradiol-(3, 1'7).

5. A -estradiol.

6. An alkali metal compound of A -estradiol.

ERWIN SCHWENK. 

